ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3935_3954dup (p.Lys1319fs) (rs1553333644)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491067 SCV000580176 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification ,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000543375 SCV000624946 pathogenic Hereditary nonpolyposis colon cancer 2017-02-27 criteria provided, single submitter clinical testing This sequence change inserts 20 nucleotides in exon 9 of the MSH6 mRNA (c.3935_3954dup20), causing a frameshift at codon 1319. This creates a premature translational stop signal in the penultimate exon of the MSH6 mRNA (p.Lys1319Leufs*15). While this is not anticipated to result in nonsense-mediated decay, it is expected to disrupt the last 42 amino acids of the MSH6 protein. This variant has not been reported in the literature in individuals with an MSH6-related disease. This variant is not expected to result in nonsense-mediated decay, but it is expected to disrupt amino acid residues Lys1319-Leu1360 of the MSH6 protein. Although no functional studies have been performed to test the effects of this particular variant on MSH6 protein function or stability, it is expected to delete the C-terminal portion of the conserved MutS domain (PMID: 17531815, 24100870). This domain is necessary for the heterodimerization of MSH6 and MSH2 (PMID: 15952900, 16464007). Two similar MSH6 variants, c.3959_3962delCAAG (p.Ala1320Glufs*6) and c.3984_3987dupGTCA (p.Leu1330Valfs*12), have been reported as Ashkenazi Jewish founder mutations known to cause Lynch syndrome (PMID: 21155762). For these reasons, this variant has been classified as Pathogenic.

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